Complement activation-related pseudoallergy caused by amphiphilic drug carriers: the role of lipoproteins.

Self-assembling amphiphilic lipids or polymers have been successfully used in pharmacotherapy as drug solvents or carriers, improving the bioavailability of water-insoluble drugs. This review focuses on an unusual hypersensitivity reaction (HSR) caused by a micellar (Cremophor EL, CrEL) and a monomeric block copolymer (poloxamer 188) representative of these systems. The HSRs, also referred to as anaphylactoid or pseudoallergic, are thought to arise as a consequence of complement (C) activation in blood. However, considering that C activation involves the deposition of multiple C and other (immune) proteins on the activator surface, the mechanism by which small, 8-25 nm CrEL micelles or individual poloxamer 188 molecules activate C is not straightforward. Observations on enlarged lipoproteins and de novo formation of abnormally large lipoprotein-like structures in plasma exposed to CrEL or poloxamer 188 raise the possibility that lipoprotein transformation might play a crucial role in C activation by these amphiphilic emulsifiers. Lipoproteins, furthermore, can also provide a negative feedback control on C activation, as suggested by the inhibition of poloxamer 188-induced C activation in the presence of excess exogenous lipoproteins, and the attenuation of liposome-induced and C activation-related hypotension in pigs by precoating the vesicles with lipoproteins. Thus, lipoproteins may be essential in the induction, and they may also play a complex modulatory role in C activation-related pseudoallergy caused amphiphilic drug solvents and carriers.